Abstract

Pancreatic cancer, primarily PDAC, is the most difficult cancer to treat. Therapeutic interventions currently available for PDAC are ineffective. Therefore, obtaining knowledge about developmental mechanisms associated with this cancer could be valuable in the development of early detection and effective treatments for pancreatic cancer.

Angiotensin II is the key effecter of the renin-angiotensin system which plays an important role in maintaining blood pressure, body fluid and electrolyte homeostasis, and collagen deposition in the stroma. Expression of the angiotensin II type 1 receptor (AT1R) is shown to be associated with the progression of multiple cancers including PDAC. On the contrary, the expression of AT2R is shown to be involved in the inhibition of the growth of multiple cancers in mice. Accordingly, the objectives of this study were to determine the potential involvement of angiotensin II receptor expression in human PDAC and to evaluate the effect of a novel AT2R agonist on the growth of murine PDAC in syngeneic mouse models. Expression of AT1R and AT2R in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using 28 surgically dissected human PDAC specimens. In this study, though a strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, AT1R expression in the PDAC area was stronger than its expression in the normal area. A moderate AT2R expression was detected in 71% of the PDAC specimens and normal area of the pancreas, and its expression levels in the two areas were similar. Both AT1R and the AT2R mRNA levels were significantly higher in the PDAC area than in the normal pancreas tissue. Cell culture studies clarified that the AT2R agonist significantly attenuated both murine and human PDAC cells with negligible cytotoxicity in normal epithelial cells. Administrations of the AT2R agonist, but not control saline, in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in the syngeneic mice. Immunohistochemical analysis of the PDAC grafts revealed that the agonist treatment induced apoptosis in tumor cells but had no effect on stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development. In addition, the novel AT2R agonist is suggested to be an effective therapeutic for the treatment of PDAC. This work was supported by the Kansas State University (KSU) Johnson Cancer Research Center, NIH RR017686, RR15563, Kansas Bioscience Authority research grant and the Greek Ministry of Education and Research and program ARISTEIA II to AGT